1. Field of the Invention
The present invention relates to devices and methods for dosing small amounts of liquid, and in particular to devices and methods which are suitable for simultaneously and accurately discharging small or extremely small amounts of dosed liquid from a plurality of parallel channels.
2. Description of Prior Art
The accurate dosing of amounts of liquid is of essential importance e.g. in the fields of pharmaceutical and biotechnological research, e.g. in the field of genomics, high-throughput screening, combinatorial chemistry and the like. Such dosing is e.g. necessary for filling so-called well-plates with reagents. In order to realize such filling various devices and methods are known at present; the most common ones of these devices are air-cushion pipettes, valve-controlled piston-displacement pipettes, piezoelectric pipettes and needle pipettes. The devices referred to are typically of the single-channel type. Part of these devices can, however, also be arranged in a raster so that parallel channels are provided. The highest degree of parallelization achieved is, at present, 384 channels in the case of some commercially available devices used for dosing volumes above 0.5 μl.
When the above-mentioned principles and devices are used for filling well-plates, one or a plurality of the problems mentioned hereinbelow frequently occur(s). In most cases, it is impossible to discharge dosing volumes which are smaller than 500 nl. This applies especially to air-cushion pipettes. In addition, the accuracy of all commercially available devices is unsatisfactory in the lower dosing range, the error exceeding typically 10%. Furthermore, due to the structural design of the conventional devices, it is impossible to achieve a high level of integration, e.g. raster dimensions of less than 4.5 mm, by said devices so that serial processing has to be carried out in some cases. Only needle pipettes are suitable for achieving also raster dimensions which are as small as 2.25 mm. If dosage is not effected in the form of a free jet, as e.g. in the case of needle pipettes, displacements and cross-contaminations of the liquids to be dosed may occur.
Known microdosage devices are described in DE-A-19706513 and in DE-A-19802368. These known devices are based on a functional principle according to which a liquid to be dosed has applied thereto an acceleration by a displacer within a pressure chamber. The pressure chamber is in fluid connection with an outlet opening and with a fluid reservoir. It follows that, when the displacer these known devices is operated, a movement of the liquid through the outlet opening as well as back into the reservoir will take place.
DE-A-19913076 discloses a microdosage device by means of which a plurality of microdroplets can be applied to a substrate; in this microdosage device the whole dosing head is acted upon by an acceleration. Due to this acceleration of the whole dosing head, an inertia-dependent relative acceleration between the fluid contained and the dosing head is achieved, said relative acceleration being of such a nature that droplets are ejected from the respective nozzle openings.
Finally, WO 00/62932 discloses methods and devices for discharging extremely small, dosed amounts of liquids, the discharge amounts mentioned being in the range of from 0.1 nl to 100 μl. According to this publication a capillary is used, which is provided with a discharge opening and which has connected thereto at least one gas line via a junction point. Via the capillary, a gas blast is introduced in the gas line so that an amount of liquid contained in the capillary section between the junction point and the discharge opening will be discharged from the discharge opening in a dosed amount. This publication also mentions the possibility of producing a pipetting array making use of a plurality of dosage devices of the type described hereinbefore. Also in the dosage devices disclosed in this publication a return flow into the reservoir takes place and, in the most disadvantageous case, air bubbles may rise into the reservoir line and block it.
The above-mentioned disadvantages result in the fact that the time which is necessary to fill a well-plate is normally considered to be too long for the desired throughput. This results, on the one hand, in high costs and, on the other hand, partly also in difficulties as far as the analysis of the reaction products is concerned, if the reactions in the individual reservoirs of the well-plate start with a time shift.
In R. Zengerle, “Mikrosysteme—Chancen für die Dosiertechnik”, wägen+dosieren 1/1996, pp. 10-15, micropumps for microdroplet injectors are disclosed in the case of which the volume of a pump chamber can be varied by means of a diaphragm which is adapted to be driven by a piezo bending transducer. An inlet opening and an outlet opening of the pressure chamber are provided. A pumping effect can be achieved in response to actuation of the diaphragm, in that either the inlet opening and the outlet opening are provided with a non-retum valve or in that a buffer is provided adjacent the pressure chamber.
DE 19648694 C1 discloses a bidirectional dynamic micropump comprising a pump chamber as well as an inlet and an outlet for the pump chamber with different flow resistances. A diaphragm borders on the pump chamber, whereby the delivery direction of the micropump can be controlled by suitably shaping the control pulse for the diaphragm.
WO 97/15394 discloses a plate having a plurality of apertures which extend therethrough. The apertures have a large opening towards one surface of the plate and a small nozzle opening towards the opposite surface of said plate. By applying a pressure on the large opening, a jet of liquid can be ejected through the small nozzle opening.
Another dosage device is known from WO 99/36176, said dosage device comprising a liquid reservoir and a channel which is in fluid communication with the liquid reservoir. Openings are formed in opposed walls of the channel so that the liquid present between the openings can be discharged, in a dosed amount, by applying a pressure to one of the openings.